Elevation in systolic blood pressure (SBP) is the leading risk factor for cardiovascular morbidity and mortality.1 Accordingly, prevention of the progression from prehypertension to sustained arterial hypertension is of critical importance.2 Microvascular rarefaction (reduced number of arterioles and capillaries) is considered one of the earliest forms of target organ damage (TOD) in hypertension, and may contribute to the development of chronic, sustained blood pressure elevation.3 4 Indeed, data from our laboratory demonstrate that target organ damage can be detected in Stage 1 hypertension and prehypertension, using the novel capillaroscopy technique to identify microvascular alterations in capillary structure and function. Prior microcirculation research in hypertension has been limited by sample size, the lack of inclusion of minority populations such as African-Americans, an ethnic population at high risk for cardiovascular morbidity and mortality, and the lack of longitudinal data. This grant proposal will extend findings from prior studies, while addressing these limitations. Recent evidence also suggests that inflammation is causally associated with hypertension (HTN).5, 6 Additionally, research to date indicates that pro-inflammatory adipokines have a negative impact on microvascular function, while adiponectin has a protective effect on the microcirculation.7 Proinflammatory adipokines may also initiate the development of endothelial dysfunction (ED) and insulin resistance (IR), two other major contributors to atherosclerotic disease.8 Insulin resistance is associated with hypertension9 and prehypertension10-12, but a causal link has not been established.13 We have generated further preliminary data specifically for this grant application that indeed demonstrates the association of pro-inflammatory measures (CRP, IL6) with microvascular function, insulin sensitivity (IS), and systolic blood pressure (SBP). Accordingly, this project is designed to test the following unified hypothesis explaining these multiple observations. Inflammatory adipokines and insulin resistance predict and may contribute to the progression of prehypertension to hypertension (Figure 1, p. 3). Positive findings from this investigation would justify future study at the molecular or cellular level, using an experimental design. We will conduct a cohort study of 340 normotensive and prehypertensive individuals recruited from a primary care practice in Philadelphia, PA. At baseline and at follow-up (1.5-2 years after enrollment x 2 visits), we will assess obesity (body mass index, BMI, waist circumference, WC, abdominal skinfold thickness, AST), adipokine levels (IL-6, TNF1, PAI-1, adiponectin), CRP, microvascular function, office blood pressure (SBP office), and insulin sensitivity (IS). 24 hour ambulatory blood pressure monitoring (ABPM) will be conducted at the baseline and final visits. Findings from this investigation will help to identify proximate causes of hypertension, potentially reducing the significant associated cardiovascular morbidity and mortality. Identification of initial components in pathways leading to vascular injury may eventually serve as clinically useful predictors for identifying patients at risk for developing microvascular and macrovascular disease, providing critical opportunities for early intervention and prevention. Early patient intervention will minimize cardiovascular risk by averting the development of irreversible vascular/endothelial damage and clinical HTN.